Solid formulation

ABSTRACT

A solid dosage form for injection and a method of making said dosage form wherein the dosage form has a moisture content of 5% (w/w) or less. The solid dosage form comprises a dried matrix including a first excipient and 0.01 to 50 (w/w) or more than 50% and up to 80% (w/w) of a therapeutic peptide; and one or more additional excipients and at least 5% (w/w) of CMC, based on the total weight of the solid dosage form, wherein the dosage form has a width of 0.5 mm to 2 mm.

FORMULATION

The present invention relates to solid dosage forms for parenteraldelivery of therapeutic peptides. In particular the solid dosage formscomprise the excipient carboxymethylcellulose (CMC) which increases thestrength, for example, compressive strength of the formulation. Thesolid dosage forms have sufficient strength to penetrate the skin of asubject without the use of a needle or cannula.

BACKGROUND

Several publications and patent documents are referenced in thisapplication in order to more fully describe the state of the art towhich this invention pertains. The disclosure of each of thesepublications and documents is incorporated by reference herein.

Injection of aqueous solutions of pharmaceuticals using a needle andsyringe is the most common method for delivery of pharmaceuticals by theparenteral route. This delivery route is used particularly for drugssuch as protein biologicals and therapeutic peptides that wouldordinarily be poorly absorbed using other routes, destroyed in thestomach or where rapid delivery is required.

However, over one third of drugs listed in the U.S. Pharmacopoeia andabout 50% of new drug molecules are insoluble and therefore cannoteasily be formulated for delivery with a needle and syringe or fortransdermal drug delivery. As a result, many drugs currently have asub-optimal formulation and many otherwise promising compounds neverreach the market.

Therefore, solid forms of drugs have been developed to attempt toovercome the short-comings of aqueous delivery by needle and syringe.

WO94/022423 (Bukh Meditec) discloses bodies of a solid pharmaceuticalcomposition having a shape and/or strength to enable penetration ofunbroken skin or mucosa of a human or an animal to deliver an activesubstance, for example, a peptide. The bodies are exemplified bycompositions comprising the excipients gelatine, agarose and gellan.There is no mention of the use of carboxymethylcellulose.

WO96/08289 (SCRAS) discloses ‘toothpick’ shaped rods for parenteraladministration having a crush strength of 8 millipoise [sic]. Theapplication discloses the use of conventional methods of manufacture butdoes not specifically discuss the techniques or refer to the use ofcarboxymethylcellulose to provide structural integrity.

WO96/03978 (Quadrant Holdings) discloses ‘glassy’ or vitreous soliddosage forms for parenteral administration. The dosage forms areprepared by heating compositions to high temperatures sufficient formelting and the formation of an amorphous, non-crystalline matrix.

WO01/26602 (Novo Nordisk) discloses an alternative method for producingelongate drug formulations for parenteral administration. Theapplication discloses that an alternative production process using highcompression forces is required to impart satisfactory strength to suchformulations. There is no disclosure of the use of excipients alone toimpart mechanical strength.

WO03/051328 (Novo Nordisk) discloses compositions for parenteraladministration comprising water-impermeable coatings to control rate ofrelease of active constituents.

WO03/023773 (Caretek Medical Limited, now Glide PharmaceuticalTechnologies Limited) discloses the use of solid rods or splinters of atherapeutic compound for parenteral drug delivery. The applicationfurther discloses the use of ‘pioneer projectiles’ to facilitate drugdelivery via the parenteral route. The document does not disclose theuse of carboxymethylcellulose to increase mechanical strength.

WO2004/075875 (Alkabello A/S) discloses non-compressed fast-dispersingsolid dosage forms comprising a saccharide matrix for oromucosaladministration.

WO2008/102136 (Glide Pharmaceutical Technologies Ltd) discloses elongatebodies and solid formulations for parenteral injection. The documentdoes not disclose the use of carboxymethylcellulose to increasemechanical strength.

EP2533814 (Ablynx NV and Glide Pharmaceutical Technologies Limited)discloses formulations for administration of immunoglobulin variabledomains which can be solid. The document does not disclose the use ofcarboxymethylcellulose, in a formulation with additional excipients, toincrease mechanical strength.

The use of such solid dosage forms for parenteral drug delivery hasseveral advantages over other delivery forms. However, whilst the use ofdrug rods and splinters generally as small as, or smaller than, a grainof rice is advantageous, there is a trade-off with the amount oftherapeutic peptide that can be incorporated whilst maintaining therequisite strength for skin penetration. Skin thickness and strengthvaries from one region of the body to another. Similarly, the thickness,hardness, moisture content and composition of underlying subcutaneoustissue will also vary, depending on sex, location on the body or age forexample. Therefore, whilst some solid dosage formulations, particularlythose with higher levels of peptide, may be able to penetrate the skinin some areas, they may not be able to be parenterally administered inothers where they are required.

Thus, there is a need for solid dosage forms that enable a range ofproportions of therapeutic peptides to be incorporated whilstmaintaining or having an increased compressive strength for skinpenetration, thereby enabling reliable delivery of the therapeuticpeptide.

SUMMARY OF THE INVENTION

The inventors have made the surprising discovery that the addition ofthe excipient carboxymethylcellulose (CMC) to solid dosage formulations,especially when the formulation is substantially dry, produces soliddosage forms that have sufficient strength for parenteraladministration.

Thus, in a first aspect of the invention there is provided a soliddosage form for injection having a moisture content of 5% (w/w) or less,the solid dosage form comprising: a dried matrix including a firstexcipient and 0.01 to 50% (w/w) of a therapeutic peptide; and one ormore additional excipients and at least 5% (w/w) of CMC, based on thetotal weight of the solid dosage form, wherein the dosage form has awidth of 0.5 mm to 2 mm.

In some embodiments, depending on the nature of the therapeutic peptide,the solid dosage forms of the invention may comprise a total of 0.5 to30% (w/w) of therapeutic peptide, for example, 0.7 to 15% (w/w) or 0.8to 10% (w/w), based on the total weight of the solid dosage form.Alternatively, the solid dosage forms of the invention may comprisehigher levels of therapeutic peptide, for example 30 to 50% (w/w) or 40to 50% (w/w), based on the total weight of the solid dosage form.

Further, even higher levels of therapeutic peptide are envisaged andhave been shown to be possible, for example in relation to octreotide orliraglutide. In some cases, the solid dosage form comprises a higherpercentage of a therapeutically effective peptide, for example more than50% (w/w) and up to 80% or more preferably more than 50% and up to 72%(w/w) or more than 50% and up to 60% (w/w).

Thus, in a further aspect of the invention, there is provided a soliddosage form for injection having a moisture content of 5% (w/w) or less,the solid dosage form comprising: a dried matrix including a firstexcipient and 50 to 80% (w/w) of a therapeutically effective peptide;and one or more additional excipients and at least 5% (w/w) of CMC,based on the total weight of the solid dosage form. Preferably, thedosage form has a width of 0.5 mm to 2 mm.

The solid dosage forms of the invention comprise at least 5% (w/w) ofCMC excipient, for example, 5 to 90% (w/w), 5 to 70% (w/w), 5 to 60%(w/w), 5 to 40% (w/w), more particularly 10 to 30% (w/w), based on thetotal weight of the solid dosage form. Particular amounts of CMC include5% (w/w), 7% (w/w), 10% (w/w), 15% (w/w), 20% (w/w), 25% (w/w), 30%(w/w), 35% (w/w), 40% (w/w), 45% (w/w), 50% (w/w), 55% (w/w), 60% (w/w),65% (w/w), 70% (w/w), 75% (w/w), 80% (w/w), 85% (w/w), 90% (w/w), basedon the total weight of the solid dosage form.

Preferably, the one or more additional excipients is a bulking agent.The bulking agent may be selected from one or more of the following:polyol, for example, mannitol or sorbitol; sugars, for example, dextranor sucrose; and amino acids.

Particularly preferred is when the bulking agent is mannitol.

The solid dosage form may further comprise one or more excipientsselected from the group comprising surfactants, sugars, amino acids,EDTA and stabilising agents.

The solid dosage forms may comprise a total of from 50 to 99.99% byweight of excipient(s), including CMC.

The term “therapeutic peptide” is used to refer to any physiologicallyor pharmaceutically active peptide that can be delivered from the soliddosage form via the parenteral route to produce a localised or systemictherapeutic effect in a human or animal.

The key classes of therapeutic peptides include somatostatins,vasopressins, platelet aggregate inhibitors, calicitonins, incretinhormones including glucagon-like peptides, and GNRH/LHRH agonists.

The solid dosage forms of the present invention are therefore useful inthe treatment or prevention of diseases or disorders which aretreated/prevented by the administration of therapeutic peptidesincluding, but not limited to, those described above.

Preferably, the therapeutic peptide consists of 100 amino acid monomersor less, for example, 5 to 60 amino acids monomers, preferably 8 to 45amino acid monomers.

Alternatively, the therapeutic peptides described herein may includechemically modified peptides, for example, peptides modified byacetylation, PEGylation, methylation, hydroxylation and albuminmodification. Other examples of chemical modifications will be known tothose skilled in the art.

The therapeutic peptide may be octreotide. Octreotide is used to treatsevere diarrhoea and other symptoms that occur with certain intestinaltumours or metastatic carcinoid tumours. Octreotide is also used totreat acromegaly.

Alternatively, the therapeutic peptide may be parathyroid hormone (PTH)or a fragment thereof such as PTH 1-34, also known as teriparatide,which is a synthetic or recombinant human 1-34 amino acid N terminalsequence of parathyroid hormone. PTH 1-34 is used to treat solitary bonecysts and hypoparathyroidism.

Alternatively, the therapeutic peptide may be exenatide or liraglutidewhich are glucagon-like peptide-1 receptor agonists, binding to the samereceptors as the endogenous metabolic hormone GLP-1 that stimulatesinsulin secretion. Such peptides may be used to treat diabetes mellitustype 2.

The term, “parenteral delivery” as used herein means that the soliddosage form is administered through the skin. Parenteral deliveryincludes subcutaneous and intramuscular administration, for example.

It will also be apparent that the solid dosage forms described hereinmay also be administered intradermally, i.e. into the skin rather thanentirely through it, or through a mucous membrane.

The solid dosage forms of the invention may also be administered bysurgery or trocar.

The solid dosage forms may be produced by extrusion. Alternatively, thesolid dosage forms may be produced by moulding or forming. The soliddosage forms may also be produced by a combination of extrusion andmoulding or extrusion and forming or extrusion and cutting.Alternatively, the dosage forms may be produced by granulation orlyophilisation.

In certain embodiments the solid dosage forms are sterilised by ionisingirradiation, for example, electron beam or gamma irradiation.Alternatively, the components of the formulation are asepticallyprocessed prior to formation of the solid dosage forms.

According to a second aspect of the invention there is provided drugdelivery devices or packaged drugs for use with a drug delivery devicewhich comprises solid dosage forms according to the first aspect.

According to a third aspect of the invention there is provided a soliddosage form according to the first aspect for use in the treatment of adisease or disorder in a subject, wherein the disease or disorder istreatable by parenteral administration of a therapeutic peptideincluding but not limited to those described above.

In a further aspect, the present invention provides use of a soliddosage form as described herein for the manufacture of a medicament forthe treatment of one or more of conditions treatable by the parenteraladministration of a therapeutic peptide including but not limited tothose described above.

In a further aspect, the present invention provides a method oftreatment of one or more conditions treatable by the therapeuticpeptides mention above which comprises administering to a subject asolid dosage form of the disclosure.

The term “treatment” is intended to embrace prophylaxis as well astherapeutic treatment. Treatment of conditions or disorders alsoembraces treatment of exacerbations thereof.

DETAILED DESCRIPTION

The prevalence of injection phobia, generally defined in terms ofability to receive an injection, has been estimated to be between 7% and22% in the general population and poses a serious challenge forhealthcare providers. The physical sensation of a prick with a needleand syringe injection is followed by the sensations of the volume offluid being pushed in and the needle being withdrawn. Usually each stepof administration is also visible.

In terms of administration efficiency, following administration, soliddosage forms enable 100% of an active material to be bioavailable. Incontrast, there is always some level of wastage with a needle andsyringe, at least a quantity of the active material being left behind inthe syringe. This allows needle-less technology to be used for high costdrugs where minimum wastage of the active drug is desired.

The use of solid dosage forms administered as needle-free or needlelessinjections is therefore advantageous since they are much quicker toadminister than traditional needle and syringe. In the context of thepresent invention, a generalised feature of the solid dosage forms isthat they are able to penetrate the skin of a subject in their ownright, replacing the requirement for a needle. Essentially the soliddosage form takes the place of the needle.

In terms of skin sensation felt during needle and syringe injection,this is primarily due to the size of needle required and the largevolume of liquid administered.

In a Phase I clinical trial the sensation felt during administration ofa solid dosage form prepared by the Applicants was found to beequivalent to the sensation felt during skin penetration with a 27-gaugeneedle (one of the standard needle sizes commonly used forvaccinations). However, following this sensation the needlelessinjection was over almost instantly because the device pushes the soliddosage form into the skin very rapidly.

Solid dosage forms and compositions of the present invention preferablyhave a maximum diameter or width of 2 mm at their widest part.Particularly the width is less than 2 mm, less than 1 mm, particularlybetween 0.50 to 0.90 mm, for example, between 0.80 and 0.90 mm.Preferably, the width is 0.85 mm with a tolerance of ±5%. As a result ofthis it has been determined that such solid dosage forms can be injectedessentially without or with very little sensation. If the diameter ofthe solid dosage forms is too small then they become very fragile anddifficult to handle as well as not being sufficiently strong topenetrate skin.

Whilst the compositions may be manufactured in any length for mostapplications, the length of the dosage form, preferably a rod shapeddosage form, is particularly less than 15 mm, less than 10 mm, less than8 mm and yet more particularly less than 6 mm, for example from 2 to 6mm, in particular 4 mm. Preferably, the length of the solid dosage formis 4 mm with a tolerance of ±5%.

However, such small scale solid dosage forms are limited in the quantityof active material that they can contain. For example, currently verythin solid dosage forms would require a very long composition in orderto contain the predetermined amount of active material. This alsoreduces the compressive strength of the composition and may cause it tobreak on administration. Thus, the dimensions of current solid dosageforms is determined by the dose of the active material and the quantityof excipients required to provide sufficient strength required for skinpenetration.

Use of the term “strength” is meant that the composition has sufficientcompressive strength to penetrate the skin of a human or animal. It hasbeen determined experimentally that a pressure force of at least 80 MPais required to reliably penetrate the epidermis of a human being withthe claimed composition. This specification was arrived at bycalculating that the mean pressure force minus 3a (i.e. three standarddeviations) should equal at least 80 MPa. Therefore, compositions forparenteral injection must be able to withstand such pressure force.

Compressive strength may be tested on a Shimadzu tensile testingmachine. Tests are carried out by formulating the composition as adosage form in the shape of a rod and applying a pressure force to thedosage form. The pressure force is increased until the dosage formbreaks. The instrument records the pressure force necessary to crush thedosage form. This parameter is termed the compressive strength andshould be understood as the breaking strength under compression. Thetests must be carried out on dosage forms which are substantially dry.

Solid dosage forms of the present invention are able to withstand apressure force of at least 80 MPa, for example, at least 100 MPa, atleast 120 MPa, at least 130 MPa, or at least 140 MPa. Typicallymeasurements are taken on formulations with a diameter of approx 0.85mm. Typically measurements are taken on solid dosage forms ofapproximately 2 mm to ensure that results are comparable betweenformulations.

The inventors have made the surprising discovery that solid dosage formscontaining CMC have a compressive strength that is higher than expected,especially when the dosage forms are substantially dry.

Use of the term “substantially dry” is meant that the solid dosage formhas minimal levels of moisture in the formulation. The moisture contentin the final solid dosage may be 5% (w/w) or less, preferably 3% (w/w)or less, more particularly, between 1 and 5% (w/w), between 1 and 3%(w/w), preferably between 2 and 3% (w/w), based on the total weight ofthe solid dosage form. Methods for analysing the moisture content in thefinal dosage form will be known to the skilled person. Suitable methodsinclude thermogravimetric analysis (TGA), Karl Fisher (KF) and infraredanalysis. The moisture present in the solid dosage may be water. Asubstantially dry dosage form can be achieved by subjecting the soliddosage form to convection drying, for example using a Memmert UF750convention oven or equivalent, followed by vacuum drying, for exampleusing a Memmert V0500 vacuum oven or equivalent. Other methods of dryingwill be known to the skilled person, for example, by drying the CMCprior to forming the solid dosage form. The other materials present inthe dosage form may also be dried prior to mixing. The moisture presentin the solid dosage form is integral to the formulation and is notconsidered a discrete active ingredient. For this reason, moisture, orwater, is not listed as an ingredient in the exemplified formulationswhich list only the ratio of ingredients used to prepare the soliddosage forms. Water can be introduced prior to extruding, in order toform a paste for ease of extrusion. This moisture is then dried off asdetailed herein. Also as mentioned herein, the level of moisture in thefinal product can be measured as a % (w/w) based on the total weight ofthe solid dosage form. It will be understood therefore that whenreferring to a % (w/w) of moisture, this is not a quantity of ingredientused to make the dosage form but a means of quantifying the level ofmoisture in the solid dosage form. Therefore, the solid dosage formsdescribed herein will include therapeutic peptide, CMC, one or moreadditional excipients and a certain amount of moisture.

The dosage forms of the present invention are preferably stable in thesense that they do not significantly change after manufacture withrespect to physical and chemical properties, e.g. potency of active,mechanical robustness and organoleptical properties like visualappearance of the dosage form.

Stability of a solid dosage form in order to ensure a sufficient shelflife of the final product may be measured with reference to the physicaland/or chemical properties of the solid dosage form or its individualconstituents. With most injectable dosages that are delivered through aneedle and syringe the formulation is stored in a liquid. However, manydrugs and vaccines are not sufficiently stable in a liquid formulationeven if they are stored in a refrigerator. In these cases the drug isthen stored as a powder and reconstituted with a diluent (typicallywater, saline or buffer) immediately before the injection. This processis complicated and in some emergency cases, such as with glucagon forthe treatment of hypoglycaemia, there are cases where the patient orcarer has injected the diluents without including the active drug.

Storing the formulations in a solid dosage form can provide enhancedshelf stability, avoid the need for cold chain storage and may providean extended shelf life. Excipients can be added to provide enhancedstability beyond just transforming a formulation from a solution to asolid. The solid dose formulations may have enhanced stability againstthermal degradation as well as enhanced stability to withstanddegradation from ionising radiation such as during sterilisation.

The term “excipient” may include binders, disintegrants, glidants,lubricants, preservatives, sorbents and vehicles. Preferred excipientsused in combination with CMC include: polyol, for example, mannitol andsorbitol; sugars, for example, dextran and sucrose; surfactants; sugars;amino acids; EDTA and stabilising agents. The solid dosage formsdescribed herein may comprise mannitol in combination with CMC. Dextranmay also be used in combination with both mannitol and CMC.

The solid dosage forms of the invention may comprise octreotide as thetherapeutic peptide. The octreotide solid dosage form will furthercomprise CMC and one or more of the additional excipients describedherein. For example, the solid dosage form may comprise between 1 and50% (w/w) of octreotide, in particular 1 and 10% (w/w), preferably 2 to5% (w/w) of octreotide, in addition to 20 to 40% (w/w), preferably 30 to40% (w/w) of CMC, and 40 to 80% (w/w), preferably 50 to 70% (w/w) of oneor more additional excipients. Alternatively, the solid dosage form maycomprise more than 50% (w/w) and up to 80% of octreotide or morepreferably more than 50% and up to 72% (w/w) or more than 50% and up to60% (w/w) of octreotide.

In particular, the one or more additional excipients is a bulking agent,which may be present in a range of 20 to 50% (w/w), preferably 30 to 40%(w/w). More preferred is when the bulking agent is mannitol.Furthermore, the octreotide solid dosage form may have a total moisturecontent of 5% (w/w) or less, preferably between 2 and 3% (w/w). Allweights are based on the total weight of the solid dosage form. Theoctreotide solid dosage form may have at least one pointed end and anelongate body and it will be appreciated that the solid dosage form mayhave any of the weight and dimensions described herein.

Alternatively, the solid dosage forms of the invention may comprise PTH1-34 as the therapeutic peptide. The PTH 1-34 solid dosage form willfurther comprise CMC and one or more of the additional excipientsdescribed herein. For example, the solid dosage form may comprisebetween 0.1 and 5 weight %, preferably 0.5 to 2.5% (w/w) of PTH 1-34, inaddition to 5 to 20% (w/w), preferably 7 to 15% (w/w) of CMC and 80 to99% (w/w), preferably 85 to 95% (w/w) of one or more additionalexcipients. In particular, the one or more additional excipients is abulking agent, which may be present in a range of 20 to 60% (w/w). Thebulking agent may be mannitol and/or dextran. Furthermore, the PTH 1-34solid dosage form may have a total moisture content of 5% or less (w/w),preferably between 2 and 3% (w/w). All weights are based on the totalweight of the solid dosage form. The PTH 1-34 solid dosage form may haveat least one pointed end and an elongate body and it will be appreciatedthat the solid dosage form may have any of the weight and dimensionsdescribed herein.

Alternatively, the solid dosage forms of the invention may compriseexenatide as the therapeutic peptide. The exenatide solid dosage formwill further comprise CMC and one or more of the additional excipientsdescribed herein. For example, the solid dosage form may comprisebetween 0.1 and 5 weight %, preferably 0.2 to 2.5% (w/w) of exenatide,in addition to 5 to 20% (w/w), preferably 7 to 15% (w/w) of CMC and 80to 99% (w/w), preferably 85 to 95% (w/w) of one or more additionalexcipients. In particular, the one or more additional excipients is abulking agent, which may be present in a range of 20 to 60% (w/w). Thebulking agent may be mannitol and/or dextran. Furthermore, the exenatidesolid dosage form may have a total moisture content of 5% or less (w/w),preferably between 2 and 3% (w/w). All weights are based on the totalweight of the solid dosage form. The exenatide solid dosage form mayhave at least one pointed end and an elongate body and it will beappreciated that the solid dosage form may have any of the weight anddimensions described herein.

Ideally all excipients used are approved for parenteral administrationor Generally Regarded As Safe (GRAS).

The solid dosage form of the invention provides a release profile thatis substantially bioequivalent to the release profile of an activematerial administered with a standard needle and syringe.

The rate of release of the active ingredient from a formulation will, tosome extent, depend of the solubility of the active ingredient. Thesolid dosage form may comprise a slow dissolving active ingredient orexcipient that also produces a controlled release of the activeingredient to the systemic circulation. The therapeutic peptide may bechosen for its particular release profile.

The addition of one or more disintegrants or controlled release agentsto the formulation may be advantageous. Suitable disintegrants andcontrolled release agents will be known to the skilled person.

The blends of excipients of this invention are used in amounts rangingfrom 50 to 99.99%, preferably 90% to 99.95%, based on the total weightof the solid dosage form.

Blends of excipients can be prepared as dry mixtures or by combiningaqueous solutions or by adding one of the two to an aqueous solution ofthe other.

The solid dosage may be formed from a bulk preparation comprising adried matrix in combination with one or more excipients. The driedmatrix comprises the therapeutic peptide in combination with one or moreexcipients, e.g. mannitol. The dried matrix may comprise up to 80% (w/w)of therapeutic peptide, for example, between 1 and 80% (w/w), based onthe total weight of the dried matrix. The remaining mass of the driedmatrix is made up of one or more excipients, for example, stabilisers,which can help to stabilise the therapeutic protein.

The bulk preparation may comprise up to 90% (w/w) of the dried matrix.For example, the bulk preparation may comprise between 10 to 90% (w/w),20 to 80% (w/w), 25 to 75% (w/w) or 30 to 65% (w/w) of the dried matrixwith the remaining mass being made up of CMC and one or more additionalexcipients. Thus, if the dried matrix comprises 80% peptide and 90% ofthe dried matrix is used in the final bulk preparation formulation, theremaining being made up of CMC and other excipients, the finalcomposition of the solid dosage form will comprise 72% peptide. However,if only 75% of the same dried matrix blend is utilised the finalcomposition, the solid dosage form will comprise 60% peptide.

The solid dosage may be formed from a bulk preparation comprising afreeze dried matrix in combination with one or more excipients. Thefreeze dried matrix comprises the therapeutic peptide in combinationwith one or more excipients. The freeze dried matrix may comprise up to80% (w/w) of therapeutic peptide, for example, between 1 and 20% (w/w),based on the total weight of the freeze dried matrix. The remaining massof the freeze dried matrix is made up of one or more excipients, forexample, stabilisers, which can help to stabilise the therapeuticprotein.

The bulk preparation may comprise up to 90% (w/w) of the freeze driedmatrix. For example, the bulk preparation may comprise between 10 to 90%(w/w), 20 to 80% (w/w), 25 to 75% (w/w) or 30 to 65% (w/w) of the freezedried matrix with the remaining mass being made up of CMC and optionallyone or more additional excipients.

Generally, solid dosage forms of the present invention will have a totalweight of less than 10 mg, usually less than 5 mg, for example from 1 mgto 5 mg, particularly in the range of 1.8 to 3.2 mg.

Preferably the solid dosage forms comprises between 0.01 and 50% (w/w)of therapeutic peptide, more preferably, between 0.05 and 30% (w/w),based on the total weight of the solid dosage form. The weight of theactive material may be in the range of 3 μg to 1.5 mg. Particularweights of active material include 1 mg, 0.5 mg, 100 μg, 50 μg, 20 μg,10 μg and 3 μg or any range therebetween.

The term, ‘solid dosage form’ refers to a dosage form which is neither aliquid, nor a powder e.g. a freeze-dried powder, but is in the form of asolid formulation.

Solid dosage forms of the present invention include rods, pellets,grains, granules and splinters. The cross section may be circular,substantially circular, ellipsoid, triangular, square, or polygonal or acombination of these. The three-dimensional shape of the solid dosageforms may be cylindrical, conical or polyhedral, such as in the form ofa cuboid, prism or pyramid, or a combination of these. Preferably thesolid dosage forms will have at least one pointed end to facilitate skinpenetration. The pointed end may be formed as a cone or bevelled tipformed from two or more intersecting surfaces akin to a chisel, forexample.

When two surfaces meet at a common point (vertex) the angle betweenthem, the included angle, is particularly between 10 and 110°,particularly 10 and 90°, yet more particularly between 20 and 65° orbetween 40° and 60°. Where the tip is in the form of a cone, the topradius of the tip is preferably below half of the diameter of thecomposition as such, more preferably below a fourth of the diameter ofthe composition as such.

Preferably the solid dosage formulations of the present invention arecrystalline rather than amorphous or glassy. In certain instances, thesolid dosage forms may have or will comprise rough surfaces or have aparticular surface geometry that imparts a surface texture to the dosageform. In other words, they will not be smooth and featureless in themanner of a glass surface.

The solid dosage forms of the invention may have disintegration timesranging from 30 seconds to 1 day. The combination of excipients in thesolid dosage form may be modified to alter disintegration time.

To exert an optimal therapeutic action an active moiety should bedelivered to its site of action in an effective concentration for thedesired period. To allow reliable prediction of the therapeutic effectthe performance of the dosage form containing the active substanceshould be well characterised.

Preferably the solid dosage forms of the invention are administeredusing a technology that enables a repeatable dose of drug everyadministration, regardless of the skin type or location. Suitabledelivery systems are disclosed in the Applicant's previous applicationspublished as WO03/023773, WO04/014468 and WO06/082439, hereinincorporated by reference. For example, the solid dosage forms of theinvention are administered at and penetrate the skin at a low velocity.Particularly, the solid dosage forms are travelling at a low velocitybefore contacting and penetrating the skin.

The solid dosage forms of the present invention may be formed by methodsknown in the art.

Briefly, the solid dosage forms of the invention may be produced by amethod comprising the following steps:

-   -   (a) blending together dried therapeutic peptide, CMC and one or        more additional excipients to create a blend;    -   (b) adding water to the blend to make a paste (either before or        during extrusion);    -   (c) extruding the paste to form an extruded product;    -   (d) drying the extruded product;    -   (e) cutting the extruded product to form a solid dosage form.

Instead of extruding the paste, the paste may be moulded or formed priorto drying. Alternatively, the paste may be both extruded and mouldedprior to drying or the paste may be both extruded and formed prior todrying. Alternatively, the blended dried therapeutic peptide, CMC andone or more additional excipient (each in powder form) may be compressedinto form.

The above method can be more fully described as follows:

-   1) The therapeutic peptide is freeze dried to produce a freeze dried    matrix. One or more of the additional excipients can also be freeze    dried with the therapeutic peptide;-   2) The freeze dried matrix is then added to CMC, and optionally one    or more of the additional excipients, and then blended;-   3) The blend is mixed with water in a twin screw extruder with a die    of the required diameter to produce an extrudate;-   4) The extrudate is cut in to rods and dried in a convection oven.    The rods may be dried for about 1 to 5 hours, for example about 3    hours. The convection oven may be at a temperature of about 30 to    60° C., for example about 50° C. Preferably, the rods are dried in a    convection oven for about 3 hours at a temperature of about 50° C.;-   5) The rods are then dried in a vacuum oven at a temperature of    about 30° C. to 70° C., preferably 60° C., until a suitable    compressive strength is reached, i.e. a compressive strength of at    least 80 MPa. The resulting dried rods are substantially dry.-   6) The rods are further cut to form individual dosage forms of    desired length, e.g. from 2 to 6 mm.

A correlation has been noticed such that the lower the level of moisturein the dried dosage form, the higher the compressive strength of thedosage form.

EXAMPLES

The following examples disclose solid dosage forms of the presentinvention as described above.

Example 1—Octreotide Formulation

Component Mixture Used to Prepare Freeze Dried Matrix (FDM):

% w/w of % w/w of Excipient mixture bulk preparation Octreotide acetate12.8 3.87 Mannitol 40.77 12.33 Histidine 18.29 5.53 Methionine 18.295.53 Citric acid 9.85 2.98

Bulk Preparation:

% w/w of Excipient bulk preparation FDM 30.25% CMC   35% Mannitol 34.75%

The octreotide solid dosage forms were produced by the following method:

-   -   1. Octreotide was freeze dried with the stabilising agents        (histidine, methionine and citric acid) and mannitol as a        bulking agent, to produce a freeze dried matrix;    -   2. The freeze dried matrix (30.25% w/w) was added to CMC (35%        w/w) and mannitol (35.75% w/w) and bag blended to produce a        blend;    -   3. The blend was mixed with water in a twin screw extruder with        a die of the required diameter to produce an extrudate;    -   4. The extrudate was cut into long rods (about 10 cm in length)        and dried for 3 hours in a convection oven at 50° C.;    -   5. The rods were then further dried in a vacuum oven at 60° C.        until a suitable compressive strength was reached;    -   6. The rods were further cut to form individual dosage forms of        4 mm in length.

This method produced dosage forms with a compressive strength of >130 MPa when vacuum dried for at least 48 hours.

TABLE 1 Drying Data for Octreotide Time in +50° C. Moisture contentCompressive strength vacuum oven (hours) (%) (MPa) 0 6.0 52 24 3.8 11748 2.9 139 72 1.7 145 96 1.4 154 114 1.0 168

To obtain the drying data in Table 1, step 6 of the method above wascarried out after varying drying times in the vacuum oven (step 5) anddosage forms of 2 mm in length (rather than 4 mm) were obtained ascompressive strength is tested on 2 mm samples. To measure compressivestrength, the 2 mm long octreotide samples were compressed between twometal plates and the force required to break the sample was measured andrecorded. The data in Table 1 show that as the moisture in the product,as measured by thermogravimetric analysis (TGA), is reduced as thecompressive strength increases. When measuring the moisture by TGA, theweight loss of each sample during a temperature ramp is monitored.

Example 2—PTH 1-34 Formulation

Component Mixture Used to Produce Freeze Dried Matrix (FDM):

% w/w of % w/w of Excipient mixture bulk preparation PTH 1-34 2.66 0.93Mannitol 65.74 22.95 Histidine 16.64 5.82 Methionine 0.78 0.27 EDTA 1.220.43 NaOH 1.83 0.64 Cysteine 7.42 2.60 Citric acid monohydrate 3.71 1.31

Bulk Preparation:

% w/w of Excipient bulk preparation FDM 35% CMC 10% Mannitol 24% Dextran30% Tween 20  1%

The PTH 1-34 solid dosage forms were produced by the following method:

-   -   1. PTH 1-34 was freeze dried with the stabilising agents        (histidine, methionine, EDTA, NaOH, cycstein and citric acid        monohydrate) and mannitol as a bulking agent, to produce a        freeze dried matrix;    -   2. The freeze dried matrix (35% w/w) was added to CMC (10% w/w),        mannitol (24%), Dextran (30% w/w) and Tween 20 (1% w/w) and bag        blended to produce a blend;    -   3. The blend was mixed with water in a twin screw extruder with        a die of the required diameter to produce an extrudate;    -   4. The extrudate was cut into rods and dried for 3 hours in a        convection oven at 50° C.;    -   5. The rods were then further dried in a vacuum oven at 60° C.        until a suitable compressive strength was reached;    -   6. The rods were further cut to form individual dosage forms of        4 mm in length.

This method produced dosage forms with a compressive strength of >100MPa when vacuum dried for at least 41 hours.

TABLE 2 Drying Data for PTH 1-34 Time in +50° C. Moisture contentCompressive strength vacuum oven (hours) (%) (MPa) 0 5.6 45 17 3.5 97 233.5 98 41 2.9 110 65 2.8 117 72 2.7 114 138 1.9 125 161 1.7 122 185 2.2120

To obtain the drying data in Table 1, step 6 of the method above wascarried out after varying drying times in the vacuum oven (step 5) anddosage forms of 2 mm in length (rather than 4 mm) were obtained ascompressive strength is tested on 2 mm samples. To measure compressivestrength, the 2 mm long PTH 1-34 samples were compressed between twometal plates and the force required to break the sample as measured andrecorded. The data in Table 2 show that as the moisture in the product,as measured by thermogravimetric analysis (TGA), is reduced thecompressive strength increases. When measuring the moisture by TGA, theweight loss of each sample during a temperature ramp is monitored.

Example 3—Exenatide Formulation

Component Mixture Used to Produce Freeze Dried Matrix (FDM):

% w/w of % w/w of Excipient mixture bulk preparation Exenatide 1.50 0.50Mannitol 70.50 24.70 Histidine 16.60 5.81 Methionine 0.77 0.27 EDTA 1.400.49 NaCl 1.83 0.64 Cysteine 7.40 2.59

Bulk Preparation:

% w/w of Excipient bulk preparation FDM 35% CMC 10% Mannitol 25% Dextran30%

The exenatide solid dosage forms were produced by the following method:

-   -   Exenatide was freeze dried with the stabilising agents        (histidine, methionine, EDTA, NaCl and cysteine) and mannitol as        a bulking agent, to produce a freeze dried matrix;    -   The freeze dried matrix (35% w/w) was added to CMC (10% w/w),        mannitol (25%), Dextran (30% w/w) and bag blended to produce a        blend;    -   The blend was mixed with water in a twin screw extruder with a        die of the required diameter to produce an extrudate;    -   The extrudate was cut into rods and dried for 3 hours in a        convection oven at 50° C.;    -   The rods were then further dried in a vacuum oven at 60° C.        until a suitable compressive strength was reached;    -   The rods were further cut to form individual dosage forms of 4        mm in length.

Example 4—Octreotide Formulation

-   -   Component Mixture Used to Prepare Dried Matrix (DM):

% w/w of % w/w of Excipient mixture bulk preparation Octreotide acetate80 72 Mannitol or alternative 20 18 excipient

-   -   Bulk Preparation:

% w/w of Excipient bulk preparation DM 90 CMC 5 Mannitol 5

-   -   1. Octreotide (80%) was dried with excipients (20%)—mannitol        with one or more further optional excipients within that 20%, to        produce a dried matrix (100%)    -   2. The dried matrix (90% w/w) was added to CMC (5% w/w) and        mannitol (5% w/w) and bag blended to produce a solid dosage form        blend (100% w/w—total formulation) with 72% peptide.

Example 5—Liraglutide Formulation

Component Mixture Used to Prepare Dried Matrix (DM):

% w/w of % w/w of Excipient mixture bulk preparation Liraglutide 80 60Mannitol or alternative 20 15 excipient

Bulk Preparation:

% w/w of Excipient bulk preparation DM 75 CMC 20 Mannitol 5

-   -   1. Liraglutide (80%) was dried with excipients (20%)—mannitol        with one or more optional excipients within that 20%, to produce        a dried matrix (100%)    -   2. The dried matrix (90% w/w) was added to CMC (5% w/w) and        mannitol (5% w/w) and bag blended to produce a solid dosage form        blend (100% w/w—total formulation) with 60% peptide.

1-18. (canceled)
 19. A solid dosage form for injection having a moisturecontent of 5% (w/w) or less, the solid dosage form comprising: a driedmatrix including a first excipient and 0.01 to 50% (w/w) of atherapeutic peptide; and one or more additional excipients and at least5% (w/w) of CMC, based on the total weight of the solid dosage form,wherein the dosage form has a width of 0.5 mm to 2 mm, wherein thedosage form has at least one pointed end configured to facilitate skinpenetration, and wherein the pointed end is in the form of a cone or inthe form of a beveled tip that is formed from two or more intersectingsurfaces meeting at a common point.
 20. A solid dosage form according toclaim 19, wherein when the pointed end is in the form of the cone, thetop radius of the pointed end is less than half the diameter of thedosage form at the base of the cone.
 21. A solid dosage form accordingto claim 19, wherein when the pointed end is in the form of the cone,the top radius of the pointed end is less than one fourth of thediameter of the dosage form at the base of the cone.
 22. A solid dosageform according to claim 19, wherein when the pointed end is in the formof the beveled tip, the intersecting surfaces form an angle between 10and 110 degrees at the common point.
 23. A solid dosage form accordingto claim 19, wherein when the pointed end is in the form of the beveledtip, the intersecting surfaces form an angle between 10 and 90 degreesat the common point.
 24. A solid dosage form according to claim 19,wherein when the pointed end is in the form of the beveled tip, theintersecting surfaces form an angle between 20 and 65 degrees at thecommon point.
 25. A solid dosage form according to claim 19, whereinwhen the pointed end is in the form of the beveled tip, the intersectingsurfaces form an angle between 40 and 60 degrees at the common point.26. A solid dosage form according to claim 19, wherein the moisturecontent is between 2% and 3% (w/w).
 27. A solid dosage form according toclaim 19, wherein the first excipient and/or at least one or moreadditional excipients is a bulking agent.
 28. A solid dosage formaccording to claim 27, wherein the bulking agent is a polyol.
 29. Asolid dosage form according to claim 28, wherein the bulking agent ismannitol.
 30. A solid dosage form according to claim 19, wherein thepeptide is octreotide, PTH 1-34, exenatide or liraglutide.
 31. A soliddosage form according to claim 19, wherein the width of the dosage formis 1 mm or less.
 32. A solid dosage form according to claim 19, whereinthe width of the dosage form is 0.85 mm.
 33. A solid dosage formaccording to claim 19, wherein the length of the dosage form is from 2to 6 mm.
 34. A solid dosage form according to claim 19, wherein thelength of the dosage form is 4 mm.
 35. A solid dosage form according toclaim 19, wherein the compressive strength of the dosage form is atleast 80 MPa.
 36. A solid dosage form according to claim 19, wherein thecompressive strength of the dosage form is at least 100 MPa.
 37. A soliddosage form according to claim 19, wherein the total weight of the soliddosage form is 5 mg or less.
 38. A solid dosage form as defined in claim19 for use in the treatment or prevention of a disease or disorder. 39.A solid dosage form according to claim 38, wherein the peptide isoctreotide and the use is the treatment or prevention of intestinaltumours or metastatic carcinoid tumours or acromegaly.
 40. A soliddosage form according to claim 38, wherein the peptide is PTH or afragment thereof and the use is the treatment or prevention of solitarybone cysts or hypoparathyroidism.
 41. A solid dosage form according toclaim 38, wherein the peptide is exenatide or liraglutide and the use isthe treatment or prevention of diabetes mellitus type
 2. 42. A drugdelivery device or packaged drug for use with a drug delivery devicewhich comprises a solid dosage form according to claim
 19. 43. A methodof treating a disease or disorder, said method comprising administeringto a subject in need a therapeutically effective amount of a soliddosage form as defined in claim
 19. 44. A method of producing the soliddosage form of claim 19, the method comprising the steps of: producing adried matrix comprising a therapeutic peptide and a first excipient;adding CMC and one or more additional excipients to create a blend;adding water to the blend to make a paste; extruding the paste to forman extruded product; drying the extruded product; and cutting theextruded product to form a solid dosage form.